Abstract
Background/Aim: The aim of this study was to clarify the risk benefits of folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus ramucirumab (F-RAM) as third-line and later-line treatment for metastatic colorectal cancer (mCRC). Patients and Methods: We compared the overall survival (OS), adverse events (AEs), and cost of F-RAM to those of trifluridine/tipiracil combination tablet (TAS-102). Results: There was no significant difference in the median OS [6.1 (range=1.2-16.3) months vs. 6.1 (range=1.2-22.3) months; log-rank test, p=0.272] and treatment duration [4.0 (range=1.2-9.6) months vs. 3.5 (range=0.2-12.3) months, p=0.888] between the F-RAM (n=13) and the TAS-102 (n=36) groups. However, AEs were more frequent in the F-RAM group, and 1-year administration of F-RAM cost higher ($81,724.8 vs. $18,931.4, p<0.001). Conclusion: F-RAM as third-line and later-line treatment for mCRC has a poor risk benefit. TAS-102 should be given priority over F-RAM.
Bevacizumab (BV) or epidermal growth factor receptor (EGFR) antibody in combination with fluorouracil/leucovorin and oxaliplatin (FOLFOX) or fluorouracil/leucovorin and irinotecan (FOLFIRI) is recommended in the primary treatment for metastatic colorectal cancer (mCRC) (1-4). BV combination therapy is recommended for Ras mutation or v-raf murine sarcoma viral oncogene homolog B1 mutation colorectal cancer regardless of the primary site (5, 6). Combination of molecular-targeted agents in secondary therapy after primary therapy with BV, chemotherapy plus BV (bevacizumab beyond progression) (7), FOLFIRI plus ramucirumab (RAM) (F-RAM) combination therapy, (8, 9) and FOLFIRI plus aflibercept beta (AFL) combination therapy (10) significantly extended the overall survival time in phase III studies. Therefore, BV/RAM/AFL therapy is recommended for second-line treatment after BV. As third-line treatment in cases refractory or intolerant to fluoropyrimidine, oxaliplatin, or irinotecan, the American Society of Clinical Oncology and the National Comprehensive Cancer Center Network recommend regorafenib or trifluridine/tipiracil combination tablet (TAS-102) as third-line or later treatment for mCRC. In Japan, these drugs are used based on the results of the RECOURSE study and the CORRECT study (11-13). However, in clinical practice, F-RAM is used for not only second-line treatment but also third-line and later treatments.
The efficacy of RAM as the third-line and later-line treatment in patients with mCRC is yet to be established. Furthermore, the risk benefits for F-RAM including efficacy, adverse events (AEs) profiles, and drug costs have not been evaluated. Molecular-targeted drugs such as BV (14) and anti-EGFR antibody (e.g., cetuximab or panitumumab) are expensive, and RAM is also costly. Therefore, applying drug economics is important to lower medical expenses. Accordingly, clarifying the risk benefit of F-RAM for the third-line and later treatment of mCRC to determine its effectiveness, safety, and medical and economic superiority will be helpful in treatment selection.
In this study, we focused on the difference between F-RAM and TAS-102 for third-line and later treatment because while both regorafenib and TAS-102 are recommended as the third-line and later treatment, TAS-102 is used more often due to its fewer AEs. Angiogenesis is an important therapeutic target in colorectal carcinoma. RAM is a human IgG-1 monoclonal antibody which targets the extracellular domain of VEGF receptor 2. As the main component of TAS-102, as well as other fluoropyrimidine anticancer drugs, trifluridine inhibits thymidylate synthase and exerts tumour growth inhibitory effects by binding with DNA.
Adding RAM to a paclitaxel regimen in the second-line treatment of advanced gastric cancer is expected to provide a minimal incremental benefit at a high incremental cost per quality-adjusted life years (15), and RAM is more costly than TAS-102. This study aimed to clarify the risk benefits of F-RAM with respect to overall survival (OS), AEs, and cost in comparison with those of TAS-102 as third-line and later treatment for mCRC. We hypothesised that F-RAM has similar efficacy to TAS-102, but is less cost effective.
Patient characteristics.
Treatment duration and reasons for discontinuation at third-line and later treatment.
Patients and Methods
Patients and evaluations. We retrospectively evaluated 49 patients treated with RAM or TAS-102 as third-line and later treatment for mCRC at Ogaki Municipal Hospital (Ogaki, Japan) between October 2016 and October 2019. Patient characteristics, OS, AEs, treatment period, reasons for discontinuation, and drug cost over the treatment duration were analysed using data collected from the electronic charts and pharmacy service records. OS was defined as the interval between the initiation of F-RAM or TAS-102 administration and the date of death from any cause. AEs were evaluated according to the Common Terminology Criteria for Adverse Events, version 4.0 (16), and the most severe grades during chemotherapy were reported. The drug cost for 1 year was calculated on the basis of the amount of the drug actually used and the dosing period. Personal information was protected in the aggregated data. This study was approved by the Institutional Review Board of Ogaki Municipal Hospital (Ogaki, Japan) (approval number: 20191128-2). The need for informed consent was waived owing to the retrospective nature of the study.
Treatment protocol. FOLFIRI plus RAM: Patients received 8 mg/kg ramucirumab as a 60-min intravenous infusion, followed by FOLFIRI (150 mg/m2 intravenous irinotecan infused over 90 min followed by or concurrent with 200 mg/m2 intravenous 1-leucovorin infused over 120 min, followed by 400 mg/m2 fluorouracil given as an intravenous bolus over 2-4 min, and then 2,400 mg/m2 of fluorouracil given as a continuous infusion over 48 h) on day 1 every 2 weeks. Trifluridine/tipiracil combination tablet: TAS-102 (35 mg/m2 per dose) was administered twice daily after breakfast and dinner for 5 days, followed by 2 days rest, then again for 2 weeks, followed by a 14-day rest period. This regimen constituted one treatment cycle and was repeated every 4 weeks.
Statistical analysis. Between-group comparisons were performed using the F-test. Mann–Whitney U-test or Chi-square test of independence (Fisher's exact probability test) was used to analyse patient characteristics, AEs, and reasons for discontinuation. The Kaplan–Meier log-rank test was used to compare OS. Significance was defined as p<0.05, and all statistical analyses were performed using the EZR software (v1.30, Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) (17).
Treatment-related adverse events reported in 10% or more of treated patients in either group.
Results
Patient characteristics. The F-RAM group and the TAS-102 group comprised 13 and 36 patients, respectively. The patient characteristics are summarised in Table I. The median age of the patients in the F-RAM and the TAS-102 group was 63 (range=36-81) years and 68 (range=52-81) years, respectively. In total, 10/13 and 32/36 of patients in the F-RAM and the TAS-102 groups received F-RAM and TAS-102 as third-line treatment, respectively.
Treatment duration and reasons for discontinuation. The treatment duration in the F-RAM and the TAS-102 groups was 4.0 (range=1.2-9.6) months and 3.5 (range=0.2-12.3) months, respectively, with no significant difference (p=0.888). The treatment duration and reasons for discontinuation of F-RAM or TAS-102 are summarised in Table II. Treatment was discontinued due to progressive disease (PD), AEs, deterioration of condition, and deterioration in performance status (PS) in 6, 2, 2, and 2 patients in the F-RAM group and in 15, 1, 3, and 16 patients in the TAS-102 group, respectively. The AEs in the F-RAM group included proteinuria, while there was nausea and vomiting in the TAS-102 group.
Adverse events analysis. The AEs for the F-RAM group included leucopenia (n=8, 61.5%), neutropenia (n=8, 61.5%), peripheral sensory neuropathy (n=8, 61.5%), nausea (n=6, 46.2%), and stomatitis (n=6, 46.2%). The AEs for the TAS-102 group included neutropenia (n=24, 66.6%), anaemia (n=18, 50.0%), nausea (n=14, 38.9%), and fatigue (n=14, 38.9%). The major AEs for the F-RAM and the TAS-102 groups are summarised in Table III. Grade 3 or higher AEs in the F-RAM group included neutropenia (n=3), leucopenia (n=2), fatigue (n=1), and diarrhoea (n=1), while those in the TAS-102 group were neutropenia (n=13), leucopenia (n=3), anaemia (n=1), decreased platelet count (n=1), and nausea (n=1). Other AEs included decreased platelet count decreased (n=1), rash (n=1), paronychia (n=1), watering eyes (n=1), and thromboembolic event (n=1) in the F-RAM group, T-Bil increase (n=1), cough (n=2), dysgeusia (n=2), fever (n=2), hoarseness (n=1), peripheral sensory neuropathy (n=1), vomiting (n=1), and watering eyes (n=1) in the TAS-102 group.
Overall survival. The median OS for the F-RAM and the TAS-102 groups was 6.1 (range=1.2-16.3) months and 6.1 (range=1.2-22.3) months, respectively (log-rank test, p=0.272). Figure 1 shows the Kaplan-Meier survival curves for the OS of patients administered with F-RAM or TAS-102 as third-line and later treatment.
Drug cost. The administration of F-RAM and TAS-102 at the dose indicated in the package insert resulted in 1-year cost estimates of $81,724.8 and $18,931.4, respectively (p<0.001) (Table IV).
Kaplan–Meier survival curves of overall survival following third-line therapy with FOLFIRI plus ramucirumab and trifluridine/tipiracil combination tablet. No significant difference in survival was observed between the two groups.
Discussion
In this study, we clarified the risk benefits of F-RAM as third-line and later treatment for mCRC with respect to OS, AEs, and drug cost; we also compared them with those of TAS-102. Our results indicated equivalent OS between F-RAM and TAS-102. However, F-RAM yielded more frequent AEs such as stomatitis and proteinuria and was more expensive compared to TAS-102. F-RAM as the third-line and later treatment for mCRC has a poor risk benefit than TAS-102.
In the RAISE study, the median OS in the F-RAM group was 13.3 months whereas it was 11.7 months in the FOLFIRI group (8). Progression-free survival was also significantly longer in the F-RAM group than in the FOLFIRI group (5.7 months vs. 4.5 months). In a study by Tomoyasu et al. (18), F-RAM yielded a median OS of 17.4 months as second-line treatment and 13.0 months as third and later line. Collectively, these findings indicate the survival benefit of F-RAM. Meanwhile, in a local phase II trial of TAS-102, the OS was only 9.0 months (19). However, these studies cannot be easily compared because of the difference in patient background and number of cases. In the current study, there was no significant difference in median OS (6.1 months vs. 6.1 months) and treatment duration (4.0 months vs. 3.5 months) between the F-RAM and the TAS-102 groups, indicating a similar efficacy between F-RAM and TAS-102.
With respect to AEs, febrile neutropenia was not observed, but neutropenia was frequent. In a local phase II trial (19), the AEs of TAS-102 included neutropenia (73.1%; grade 3 or higher, 51.3%) and pyrogenic neutropenia (4.2%). Nausea was also frequent and was experienced by as high as 63% of patients; 52.9% and 54.0% of patients also experienced fatigue and anorexia. These findings were consistent with that in the present study. Nausea, fatigue, and anorexia all reduced the patients' quality of life (QOL), and thus it is necessary to carefully determine the continuation of treatment. The rate of AEs in the F-RAM group in this study was similar to that in the RAISE study. The AEs included bone marrow suppression, gastrointestinal toxicity such as nausea and diarrhoea, stomatitis, and proteinuria. The high rate of peripheral sensory neuropathy in this study may be due to pre-treatment with an oxaliplatin-based regimen in all patients, and not directly due to evaluated drugs. Peripheral sensory neuropathy was more frequent in the F-RAM group than in the TAS-102 group, but this may also be influenced by the administration of irinotecan. Notably, the rate of bone marrow suppression, nausea, and fatigue was similar between the two treatment groups, but other AEs in the F-RAM group such as proteinuria, diarrhoea, and stomatitis were not observed in the TAS-102 group. There were also cases in which RAM was not used due to proteinuria. Diarrhoea and stomatitis as adverse events reduce the patients' QOL (20), and thus AE management is important. Collectively, these findings show that F-RAM yields frequently higher AEs that lower the patients' QOL than TAS-102.
Annual drug cost.
The high medical costs of cancer care have been often discussed (21). The usefulness of RAM in clinical practice has been questioned given its high cost, availability of alternative options, and minimal survival improvement (22). In this study, F-RAM had low cost effectiveness; the 1-year estimated cost for F-RAM was markedly higher than that for TAS-102 ($81,724.8 vs. $18,931.4). Goldstein et al. is currently using RAM in advanced gastric cancer. The Gastrointestinal Oncology Group has decided not to use ramucirumab for colorectal cancer at the current price (23).
With respect to cost, TAS-102 is a more reasonable option than F-RAM. Ideally, F-RAM should only be considered in mCRC patients with good PS after treatment with TAS-102 or regorafenib. Further, the management of diarrhoea and stomatitis as adverse events of F-RAM should be decided cautiously.
Despite the limited number of cases and differences in patient background, our study clearly showed that TAS-102 is more economically beneficial than F-RAM. Our findings provide novel insights into the characteristics of F-RAM and TAS-102 for the treatment of patients with mCRC and can guide decision making for the appropriate third-line and later treatment drug in mCRC. Neutropenia at the time of cancer chemotherapy may be associated with favourable prognosis, and thus future studies should evaluate whether neutropenia during F-RAM treatment could also indicate favourable prognosis. Further, BV, RAM, and AFL are all used in second-line treatment; accordingly, selection criteria for identifying those who will optimally benefit from using these drugs as second-line treatment need to be established. Moreover, their feasibility and efficacy as third-line and later treatment should also be investigated.
In conclusion, F-RAM as third-line and later treatment for mCRC has a poor risk benefit. TAS-102 should be given priority over F-RAM in third-line and later treatment for mCRC.
Footnotes
Authors' Contributions
MK contributed to the case report design, collected and provided data, was the principal author of the article, and is the guarantor of the article and all data. EU, HT, and TY contributed to the clinical studies design, reviewed the article, and supervised the report and publication process. All Authors approved the final version of the article.
Conflicts of Interest
The Authors declare no conflicts of interest.
- Received December 3, 2019.
- Revision received February 4, 2020.
- Accepted February 5, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
